Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43

M Sarasin-Filipowicz, X Wang, M Yan… - … and cellular biology, 2009 - Taylor & Francis
M Sarasin-Filipowicz, X Wang, M Yan, FHT Duong, V Poli, DJ Hilton, DE Zhang, MH Heim
Molecular and cellular biology, 2009Taylor & Francis
Recombinant alpha interferon (IFN-α) is used for the treatment of viral hepatitis and some
forms of cancer. During these therapies IFN-α is injected once daily or every second day for
several months. Recently, the long-acting pegylated IFN-α (pegIFN-α) has replaced
standard IFN-α in therapies of chronic hepatitis C because it is more effective, supposedly by
inducing a long-lasting activation of IFN signaling pathways. IFN signaling in cultured cells,
however, becomes refractory within hours, and little is known about the pharmacodynamic …
Recombinant alpha interferon (IFN-α) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-α is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-α (pegIFN-α) has replaced standard IFN-α in therapies of chronic hepatitis C because it is more effective, supposedly by inducing a long-lasting activation of IFN signaling pathways. IFN signaling in cultured cells, however, becomes refractory within hours, and little is known about the pharmacodynamic effects of continuously high IFN-α serum concentrations. To investigate the behavior of the IFN system in vivo, we repeatedly injected mice with IFN-α and analyzed its effects in the liver. Within hours after the first injection, IFN-α signaling became refractory to further stimulation. The negative regulator SOCS1 was rapidly upregulated and likely responsible for early termination of IFN-α signaling. For long-lasting refractoriness, neither SOCS1 nor SOCS3 were instrumental. Instead, we identified the inhibitor USP18/UBP43 as the key mediator. Our results indicate that the current therapeutic practice using long-lasting pegIFN-α is not well adapted to the intrinsic properties of the IFN system. Targeting USP18 expression may allow to exploit the full therapeutic potential of recombinant IFN-α.
Taylor & Francis Online